Long term Glycemic Control Using Polymer Encapsulated, Human Stem-Cell Derived β-cells in Immune Competent mice

The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in diabetic patients1. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically2, but are limited by the adverse effects of lifetime immunosuppression and the limited supply of donor tissue3. The latter concern may be addressed by recently described glucose responsive mature β-cells derived from human embryonic stem cells; called SC-β, these cells may represent an unlimited human cell source for pancreas replacement therapy4. Strategies to address the immunosuppression concern include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier5,6. However, clinical implementation has been challenging due to host immune responses to implant materials7. Here, we report the first long term glycemic correction of a diabetic, immune-competent animal model with human SC-β cells. SC-β cells were encapsulated with alginate-derivatives capable of mitigating foreign body responses in vivo, and implanted into the intraperitoneal (IP) space of streptozotocin-treated (STZ) C57BL/6J mice. These implants induced glycemic correction until removal at 174 days without any immunosuppression. Human C-peptide concentrations and in vivo glucose responsiveness demonstrate therapeutically relevant glycemic control. Implants retrieved after 174 days contained viable insulin-producing cells

Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates

The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response.Leona M. and Harry B. Helmsley Charitable Trust (3-SRA-2014-285-M-R)United States. National Institutes of Health (EB000244)United States. National Institutes of Health (EB000351)United States. National Institutes of Health (DE013023)United States. National Institutes of Health (CA151884)United States. National Institutes of Health (P41EB015871-27)National Cancer Institute (U.S.) (P30-CA14051

Long-term glycemic control using polymer-encapsulated human stem cell–derived beta cells in immune-competent mice

The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-β cells), which may represent an unlimited source of human cells for pancreas replacement therapy. Strategies to address the immunosuppression concerns include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier. However, clinical implementation has been challenging because of host immune responses to the implant materials. Here we report the first long-term glycemic correction of a diabetic, immunocompetent animal model using human SC-β cells. SC-β cells were encapsulated with alginate derivatives capable of mitigating foreign-body responses in vivo and implanted into the intraperitoneal space of C57BL/6J mice treated with streptozotocin, which is an animal model for chemically induced type 1 diabetes. These implants induced glycemic correction without any immunosuppression until their removal at 174 d after implantation. Human C-peptide concentrations and in vivo glucose responsiveness demonstrated therapeutically relevant glycemic control. Implants retrieved after 174 d contained viable insulin-producing cells.Leona M. and Harry B. Helmsley Charitable Trust (Grant 3-SRA-2014-285-M-R)National Institutes of Health (U.S.) (Grants EB000244, EB000351, DE013023, and CA151884)Tayebati Family FoundationUnited States. Dept. of Defense. Congressionally Directed Medical Research Programs (Grant W81XWH-13-1-0215)Juvenile Diabetes Research Foundation International (Grant 3-2013-178

Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates

siRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ∼ 0.002 mg/kg), rats (ED50 < 0.01 mg/kg), and nonhuman primates (over 95% silencing at 0.3 mg/kg). Apolipoprotein E plays a significant role in the potency of cKK-E12 both in vitro and in vivo. cKK-E12 was highly selective toward liver parenchymal cell in vivo, with orders of magnitude lower doses needed to silence in hepatocytes compared with endothelial cells and immune cells in different organs. Toxicity studies showed that cKK-E12 was well tolerated in rats at a dose of 1 mg/kg (over 100-fold higher than the ED50). To our knowledge, this is the most efficacious and selective nonviral siRNA delivery system for gene silencing in hepatocytes reported to date.Alnylam Pharmaceuticals (Firm)National Institutes of Health (U.S.) (NIH Grant R01-EB000244-27)National Institutes of Health (U.S.) (NIH Grant 5-R01-CA132091-04)National Institutes of Health (U.S.) (Postdoctoral Fellowship

Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques

The transplantation of pancreatic islet cells could restore glycaemic control in patients with type 1 diabetes. Microspheres for islet encapsulation have enabled long-term glycaemic control in rodent models of diabetes; however, humans transplanted with equivalent microsphere formulations have experienced only transient islet graft function owing to a vigorous foreign-body response (FBR), to pericapsular fibrotic overgrowth (PFO) and, in upright bipedal species, to the sedimentation of the microspheres within the peritoneal cavity. Here, we report the results of the testing in non-human primate (NHP) models of seven alginate formulations that were efficacious in rodents, including three that led to transient islet graft function in clinical trials. All formulations elicited significant FBR and PFO 1 month post implantation; however, three chemically modified, immune-modulating alginate formulations elicited a reduced FBR. In conjunction with a minimally invasive transplantation technique into the bursa omentalis of NHPs, the most promising chemically modified alginate derivative (Z1-Y15) protected viable and glucose-responsive allogeneic islets for 4 months without the need for immunosuppression. Chemically modified alginate formulations may enable the long-term transplantation of islets for the correction of insulin deficiency.National Institutes of Health (U.S.) (Grant EB000244)National Institutes of Health (U.S.) (Grant EB000351)National Institutes of Health (U.S.) (Grant DE013023)National Institutes of Health (U.S.) (Grant CA151884

Changing the rules of the game: an analysis of EU influence on electricity and gas liberalization: with a focus on the Baltic Sea Region, and future challenges to EU energy market regulation

This study analyses the expansion of the EU into energy market regulation. It shows that the limits to EU influence and, thereby, EU energy market regulation for the internal energy market, begin where EU influence affects national interests with regard to ensuring energy security. This scientifically established insight bears an important practical implication. The further development of EU energy market regulation as a cornerstone of the internal energy market faces a particular policy challenge: It is necessary to establish a regulatory framework for the internal electricity and gas market, which acknowledges the primacy of national energy security interests. This finding is important in the light of the new and increasing energy policy challenges that some Member States face today, not least as a result of a liberalized energy market. Moreover, in the context of new systemic risks arising from ongoing energy market integration, a politically unstable (in the worst case - collapsing) EU regulatory framework can cause significant social and economic costs for individual Member States. With regard to that, the study points to the increasingly complex policy areas that are made subject to EU integration and calls for more attention to the related regulatory and political risks - also with a view to the current euro crisis. Diese Studie analysiert die Expansion der EU in die Energiemarktregulierung. Sie zeigt, dass die Grenzen des EU Einflusses und damit des EU Regulierungsrahmens für den Energiebinnenmarkt dort beginnen, wo nationale Interessen mit Blick auf die Gewährleistung der Energieversorgungssicherheit tangiert werden. Diese Erkenntnis hat eine wichtige praktische Implikation. Die weitere Ausgestaltung der EU Energiemarktregulierung und damit des Fundaments des Energiebinnenmarktes steht vor einer besonderen politischen Herausforderung: Es gilt einen stabilen gemeinschaftlichen Regulierungsrahmens für den europäischen Strom- und Gasmarkt unter dem Primat nationaler Energiesicherheitsinteressen bereitzustellen. Dies ist von Bedeutung im Lichte wachsender und neuer energiepolitischer Herausforderungen für die einzelnen Mitgliedstaaten, nicht zuletzt als Folge eines liberalisierten Energiemarktes. In Anbetracht neuer systemischer Risiken, die sich aus einem integrierten europäischen Energiemarkt ergeben, kann ein politisch instabiler (im schlimmsten Fall kollabierender) gemeinschaftlicher Regulierungsrahmen für die Mitgliedstaaten hohe soziale und ökonomische Kosten nach sich ziehen. An dieser Stelle verweist die Studie auf die immer komplexeren Integrationsgegenstände der EU und fordert, dass den damit einhergehenden Risiken, regulatorischer und politischer Art, grössere Aufmerksamkeit zu schenken ist - gerade auch mit Blick auf die aktuelle Krise der Gemeinschaftswährung